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Primary glioblastoma cells for precision medicine : a quantitative portrait of genomic (in)stability during the first 30 passages
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- Baskaran, Sathishkumar (author)
- Uppsala universitet,Neuroonkologi
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- Mayrhofer, Markus, 1981- (author)
- Uppsala universitet,Cancerfarmakologi och beräkningsmedicin,Science for Life Laboratory, SciLifeLab
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- Göransson Kultima, Hanna (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Institutionen för medicinska vetenskaper
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- (creator_code:org_t)
- 2018-02-15
- 2018
- English.
- In: Neuro-Oncology. - : OXFORD UNIV PRESS INC. - 1522-8517 .- 1523-5866. ; 20:8, s. 1080-1091
- Journal article (peer-reviewed)
Abstract
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- Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Keyword
- aneuploidy
- clones
- GBM DNA methylation
- GBM subtype
- glioma stem cell cultures
- patient derived GBM cell cultures
- systems biology
Publication and Content Type
- ref (subject category)
- art (subject category)
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